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PubMed2000

The Xenopus homologue of Bicaudal-C is a localized maternal mRNA that can induce endoderm formation.

In Xenopus, zygotic transcription starts 6 hours after fertilization at the midblastula transition and therefore the first steps in embryonic development are regulated by maternally inherited proteins and mRNAs. While animal-vegetal polarity is already present in the oocyte, the dorsoventral axis is only established upon fertilization by the entry of the sperm and the subsequent rotation of the egg cortex. In a screen for maternal mRNAs whose stability is regulated by this cortical rotation, we isolated the Xenopus homologue of the Drosophila gene Bicaudal-C (xBic-C). It encodes a putative RNA-binding molecule expressed maternally and localized predominantly to the vegetal half of the egg. Upon fertilization and cortical rotation, xBic-C mRNA is displaced together with the heavy yolk towards the future dorsal side of the embryo. In UV-ventralized embryos, xBic-C is polyadenylated less than in untreated embryos that undergo cortical rotation. Overexpression of xBic-C by injection of synthetic mRNA in whole embryos or in ectodermal explants leads to ectopic endoderm formation. This endoderm-inducing activity is dependent on the presence of the RNA-binding domain of the protein. In contrast to the two other known maternally encoded endoderm inducers, Vg1 and VegT, xBic-C ectopic expression leads specifically to endoderm formation in the absence of mesoderm induction.

Amino Acid Sequence↗
PubMed2000

An FGF signal from endoderm and localized factors in the posterior-vegetal egg cytoplasm pattern the mesodermal tissues in the ascidian embryo.

The major mesodermal tissues of ascidian larvae are muscle, notochord and mesenchyme. They are derived from the marginal zone surrounding the endoderm area in the vegetal hemisphere. Muscle fate is specified by localized ooplasmic determinants, whereas specification of notochord and mesenchyme requires inducing signals from endoderm at the 32-cell stage. In the present study, we demonstrated that all endoderm precursors were able to induce formation of notochord and mesenchyme cells in presumptive notochord and mesenchyme blastomeres, respectively, indicating that the type of tissue induced depends on differences in the responsiveness of the signal-receiving blastomeres. Basic fibroblast growth factor (bFGF), but not activin A, induced formation of mesenchyme cells as well as notochord cells. Treatment of mesenchyme-muscle precursors isolated from early 32-cell embryos with bFGF promoted mesenchyme fate and suppressed muscle fate, which is a default fate assigned by the posterior-vegetal cytoplasm (PVC) of the eggs. The sensitivity of the mesenchyme precursors to bFGF reached a maximum at the 32-cell stage, and the time required for effective induction of mesenchyme cells was only 10 minutes, features similar to those of notochord induction. These results support the idea that the distinct tissue types, notochord and mesenchyme, are induced by the same signaling molecule originating from endoderm precursors. We also demonstrated that the PVC causes the difference in the responsiveness of notochord and mesenchyme precursor blastomeres. Removal of the PVC resulted in loss of mesenchyme and in ectopic notochord formation. In contrast, transplantation of the PVC led to ectopic formation of mesenchyme cells and loss of notochord. Thus, in normal development, notochord is induced by an FGF-like signal in the anterior margin of the vegetal hemisphere, where PVC is absent, and mesenchyme is induced by an FGF-like signal in the posterior margin, where PVC is present. The whole picture of mesodermal patterning in ascidian embryos is now known. We also discuss the importance of FGF induced asymmetric divisions, of notochord and mesenchyme precursor blastomeres at the 64-cell stage.

Actins↗
PubMed2000

Formation of the definitive endoderm in mouse is a Smad2-dependent process.

TGFbeta growth factors specify cell fate and establish the body plan during early vertebrate development. Diverse cellular responses are elicited via interactions with specific cell surface receptor kinases that in turn activate Smad effector proteins. Smad2-dependent signals arising in the extraembryonic tissues of early mouse embryos serve to restrict the site of primitive streak formation and establish anteroposterior identity in the epiblast. Here we have generated chimeric embryos using lacZ-marked Smad2-deficient ES cells. Smad2 mutant cells extensively colonize ectodermal and mesodermal populations without disturbing normal development, but are not recruited into the definitive endoderm lineage during gastrulation. These experiments provide the first evidence that TGFbeta signaling pathways are required for specification of the definitive endoderm lineage in mammals and identify Smad2 as a key mediator that directs epiblast derivatives towards an endodermal as opposed to a mesodermal fate. In largely Smad2-deficient chimeras, asymmetric nodal gene expression is maintained and expression of pitx2, a nodal target, is also unaffected. These results strongly suggest that other Smad(s) act downstream of Nodal signals in mesodermal populations. We found Smad2 and Smad3 transcripts both broadly expressed in derivatives of the epiblast. However, Smad2 and not Smad3 mRNA is expressed in the visceral endoderm, potentially explaining why the primary defect in Smad2 mutant embryos originates in this cell population.

Animals↗
PubMed2001

Foregut endoderm is required at head process stages for anteriormost neural patterning in chick.

Anterior definitive endoderm, the future pharynx and foregut lining, emerges from the anterior primitive streak and Hensen's node as a cell monolayer that replaces hypoblast during chick gastrulation. At early head process stages (4+ to 6; Hamburger and Hamilton) it lies beneath, lateral to and ahead of the ingressed axial mesoderm. Removal of the monolayer beneath and ahead of the node at stage 4 is followed by normal development, the removed cells being replaced by further ingressing cells from the node. However, similar removal during stages 4+ and 5 results in a permanent window denuded of definitive endoderm, beneath prechordal mesoderm and a variable sector of anterior notochord. The foregut tunnel then fails to form, heart development is confined to separated lateral regions, and the neural tube undergoes no ventral flexures at the normal positions in brain structure. Reduction in forebrain pattern is evident by the 12-somite stage, with most neuraxes lacking telencephalon and eyes, while forebrain expressions of the transcription factor genes GANF and BF1, and of FGF8, are absent or severely reduced. When the foregut endoderm removal is delayed until stage 6, later forebrain pattern appears once again complete, despite lack of foregut formation, of ventral flexure and of heart migration. Important gene expressions within axial mesoderm (chordin, Shh and BMP7) appear unaffected in all embryos, including those due to be pattern-deleted, during the hours following the operation when anterior brain pattern is believed to be determined. A specific system of neural anterior patterning signals, rather than an anterior sector of the initially neurally induced area, is lost following operation. Heterotopic lower layer replacement operations strongly suggest that these patterning signals are positionally specific to anteriormost presumptive foregut. The homeobox gene Hex and the chick Frizbee homologue Crescent are both expressed prominently within anterior definitive endoderm at the time when removal of this tissue results in forebrain defects, and the possible implications of this are discussed. The experiments also demonstrate how stomodeal ectoderm, the tissue that will, much later, form Rathke's pouch and the anterior pituitary, is independently specified by anteriormost lower layer signals at an early stage.

Animals↗
PubMed2002

Mezzo, a paired-like homeobox protein is an immediate target of Nodal signalling and regulates endoderm specification in zebrafish.

Endoderm specification in zebrafish is mediated by the zygotic transcription factors Bon/Mixer, Faust/Gata5, Casanova and Sox17, whose expression is induced by Nodal signalling. Bon/Mixer and Gata5 require Casanova in order to promote endoderm formation and all three factors act upstream of sox17, but it is not clear whether Casanova acts downstream of or in parallel to Bon/Mixer and Gata5. An additional factor induced at the margin of the blastoderm by Nodal signalling is thought to be required to induce casanova expression. We show that Mezzo, a novel paired-like homeobox protein, may be this missing transcription factor. The homeobox of Mezzo is mostly related to the homeodomain of the Mix-like and Mixer homeoproteins, but Mezzo is distinct from Bon/Mixer, the product of the bonnie and clyde gene. Like bon/mixer, mezzo is expressed transiently in mesendoderm precursors. By analysing the expression of mezzo in various mutants of Nodal signalling, we show that its expression strictly depends on a functional Nodal signalling pathway. By expressing a constitutively active Nodal receptor in the presence of translation inhibitors, we further demonstrate that mezzo, bonnie and clyde, and casanova are all immediate early targets of Nodal signalling, while sox17 requires post-MBT protein synthesis in order to be induced. Overexpression of mezzo mRNA can induce ectopic expression of casanova and sox17 and can also turn on the pan mesodermal marker gene ntl. We show that the function of mezzo is redundant with that of bonnie and clyde and that mezzo RNA can partially rescue bonnie and clyde mutants. Injection of antisense Morpholino oligonucleotides targeted against mezzo into bonnie and clyde mutant embryos abolishes all sox17 expression and aggravates their mutant phenotype. These results highlight the complexity of the transcriptional network operating during endoderm formation. They place mezzo as a new transcription factor with unique properties acting in parallel with bonnie and clyde, faust and casanova in the Nodal signalling pathway that controls specification of mesoderm and endoderm in zebrafish.

Amino Acid Sequence↗
PubMed2002

Insufficient VEGFA activity in yolk sac endoderm compromises haematopoietic and endothelial differentiation.

Vascular endothelial growth factor A (VEGFA) plays a pivotal role in the first steps of endothelial and haematopoietic development in the yolk sac, as well as in the establishment of the cardiovascular system of the embryo. At the onset of gastrulation, VEGFA is primarily expressed in the yolk sac visceral endoderm and in the yolk sac mesothelium. We report the generation and analysis of a Vegf hypomorphic allele, Vegf(lo). Animals heterozygous for the targeted mutation are viable. Homozygous embryos, however, die at 9.0 dpc because of severe abnormalities in the yolk sac vasculature and deficiencies in the development of the dorsal aortae. We find that providing 'Vegf wild-type' visceral endoderm to the hypomorphic embryos restores normal blood and endothelial differentiation in the yolk sac, but does not rescue the phenotype in the embryo proper. In the opposite situation, however, when Vegf hypomorphic visceral endoderm is provided to a wild-type embryo, the 'Vegf wild-type' yolk sac mesoderm is not sufficient to support proper vessel formation and haematopoietic differentiation in this extra-embryonic membrane. These findings demonstrate that VEGFA expression in the visceral endoderm is absolutely required for the normal expansion and organisation of both the endothelial and haematopoietic lineages in the early sites of vessel and blood formation. However, normal VEGFA expression in the yolk sac mesoderm alone is not sufficient for supporting the proper development of the early vascular and haematopoietic system.

3' Untranslated Regions↗
PubMed1979

Gap and septate junctions in the excitable endoderm of Polyorchis penicillatus (Hydrozoa, Anthomedusae).

The morphological basis of impulse conduction in a jellyfish epithelium was investigated. Lanthanum impregnation of endodermal canal and endodermal lamella verified the existence of true gap junctions in Polyorchis. In both transverse and en face sections of gap junctions, electron-lucent globules, with a width of 7--8 nm and a spacing of about 11 nm, are evident. Gap-junctions are concentrated at the peripheral canal margin and septate junctions are localized around the canal lumen. Epithelial cells of the endodermal canals are capable of conducting a non-decrementing action potential. It is suggested that endodermal spike propagation, which can mediate 'crumpling' behaviour, is dependent upon low-resistence ionic pathways provided by gap-junctions and upon sealing of the intercellular space from saline extracellular fluids by septate junctions.

Action Potentials↗
PubMed1982

Morphometric analysis of the visceral yolk sac endoderm in the rat in vivo and in vitro.

Rat embryos together with their visceral yolk sac were grown in vitro during the early period of organogenesis from days 9.5 to 11.5 and the ultrastructural morphology od the visceral yolk sac cells was compared with that in vivo at the beginning and at the end of the culture period. Identical areas of the visceral yolk sac endodermal cells were analysed morphometrically. A measure of the functional activity was obtained by comparison of the volume density of surface density of the vacoular system. At 9.5 and 11.5 days, the values obtained were virtually identical for yolk sacs in vivo and in vitro. At 9.5 days, the volume and surface density of the endocytotic vacuoles in the embryonic endoderm was significantly lower than in the visceral yolk sac endoderm. It is concluded that the digestive function of the yolk sac is almost certainly identical in culture and in vivo and that the cells of the embryonic endoderm do not take a significant part in embryonic nutrition.

Animals↗
PubMed1997

Differentiation of biliary epithelial cells from the mouse hepatic endodermal cells cultured in vitro.

Differentiation of biliary epithelial cells from hepatic endodermal cells of the mouse embryo was examined with a special attention to the role of the connective tissue. When the whole liver primordium of the 9.5-day mouse embryo was cultured in vitro for 5 days, the endodermal cells differentiated into mature hepatocytes expressing carbamoylphosphate synthetase I (CPSI) and accumulating glycogen. Intrahepatic bile duct cells and connective tissue were poorly developed in this culture. However, when the hepatic endoderm was recombined with the 4-day embryonic chick lung mesenchyme and cultured in vitro, the endodermal cells differentiated into many ductal epithelial cells as well as mature hepatocytes with abundant connective tissue development. These results suggest that the ducts might be bile ducts, and that connective tissue is very important for bile duct development. In addition, this in vitro culture system might be useful for the study of mechanisms of bile duct differentiation and congenital biliary atresia.

Animals↗
PubMed1986

Surface morphology of the human yolk sac: endoderm and mesothelium.

The yolk sac of human embryos from the 5th to 7th week of gestation was first revealed under the scanning electron microscope (SEM) with complementary observations under the transmission electron microscope (TEM). The inner and outer surfaces of the human yolk sac basically showed profiles similar to those of other mammalian yolk sacs reported by previous workers. The free surface of the endodermal cell measured 10-15 microns in diameter and was only slightly swollen in its earlier stages, possessing microvilli of 100-600 nm in length. On the other hand, the outer surface of mesothelial cells was swollen, but much smaller in size (8-10 microns). The mesothelial microvilli were much longer than those of the endoderm, measuring about 1.5 micron in length. On the endodermal surface, ruffles and various sizes of holes with short microvilli were occasionally found. The latter became larger with development, and seemed to be continuous with the endodermal tubules.

Endoderm↗
PubMed1976

Intimate contact between human yolk sac endoderm and haemopoietic precursor cells.

Although the localization of embryonic haemopoietic cells in the endodermal epithelium of the human yolk sac had been discovered several decades ago, the nature and significance of the localization were dubious, and it was supposed that light microscopic pictures represent technical artifacts. Our ultamicrographs now demonstrate that at 16--26 mm CR-length there is an intimate contact between yolk sac endoderm and free haemopoietic precursor cells: apart from interdigitations various types of intercellular contact could be discovered. These contacts, especially the gap-like ones with associated electron dense cytoplasmic areas speak for intercellular communication, i.e., the role of endoderm in early human embryonic haematopoiesis appears likely. The demonstrability of these contacts, however, does not mean that endodermal associations are indispensable for haemopoietic differentiation.

Endoderm↗
PubMed2003

Origin and evolution of endoderm and mesoderm.

Germ layers are defined as cell layers that arise during early animal development, mostly during gastrulation, and that give rise to all tissues and organs in adults. The evolutionary origin of the inner germ layers, endoderm and mesoderm, and their relationship have been a matter of debate for decades. In this review we summarize the major modes of endoderm and mesoderm formation found in Metazoa and possible evolutionary scenarios to reconstruct the ancestral state. In the second part, we address the question whether endoderm as well as mesoderm are homologous among Bilateria. In this regard, we propose that the comparative analysis of some crucial transcription factors involved in the early specification and differentiation of these germ layers might provide cues for the level of homology. We focus on four classes of genes: the Zn-finger gene GATA 4-6, the bHLH gene twist, the Krüppel-like Zn-finger gene snail and the T-box gene brachyury. The role of each of these genes in mesendoderm formation is summarized and we propose that the specific function of each of these genes in endoderm and mesoderm formation evolved from the regulation of basic cellular features, such as cell adhesion, cell motility, cytoskeleton and cell cycle.

Animals↗
PubMed1989

F9 teratocarcinoma aggregates express villin upon differentiation into visceral endoderm-like cells.

The visceral endoderm of the mouse embryo is a polarized epithelium which has recently been shown to express villin, a major actin binding component of absorptive epitheliums. We report here that villin is induced during differentiation of aggregates of the mouse embryonal carcinoma F9, an in vitro system widely used to study extraembryonic endoderm differentiation. Identical results were obtained with a variant of F9 which carries an immortalizing vector. Villin is coexpressed with F-actin and with alpha-foetoprotein, in most of the visceral endoderm-like cells lining the aggregates. This system is potentially useful to study (i) the induction of villin expression and (ii) the establishment of polarity in the visceral endoderm epithelium.

Animals↗
PubMed1979

An analysis of the aggregation and morphogenesis of area opaca endoderm cells from the primitive-streak chick embryo.

The aggregative behaviour and subsequent morphogenesis of extra-embryonic endoderm cells from primitive-streak chick embryos have been investigated. A relatively pure population of area opaca endoderm cells was obtained by differential dissociation, which involves partial separation of epiblast and endoderm cell clumps by sieving through Nitex mesh. For aggregation studies cells were cultured in rotating flasks in Leibovitz (L-15) medium, in saline or in saline supplemented with glucose (1 mg/ml). Aggregation was monitored using the Coulter Counter. In these three media aggregation is rapid; by 10 min an average of 61% of the population had aggregated, to reach a plateau at 30 min when an average percent adhesion value of 83% was obtained. The aggregates in L-15 medium were large and compact. After several days in culture, they cavitated and formed smooth hollow vesicles with thin walls composed of one or a few cell layers. Aggregates formed in PCS were smaller and looser in appearance; the addition of glucose resulted in a certain degree of compaction. Some morphogenesis occurred under these conditions with the aggregates developing numerous irregular cavities. These experiments suggest that some of the factors that affect cell adhesion in early embryonic cells can be studied in vitro. The results also indicate that the ability to cavitate is an intrinsic property of the endoderm cells of the area opaca since this occurs in the absence of epiblast or mesoderm.

Animals↗
PubMed1996

Developmental expression and vitamin D regulation of calbindin-D28K in chick embryonic yolk sac endoderm.

The yolk is an important calcium source for the developing chick embryo. The epithelial yolk sac endodermal cells lie in direct contact with the yolk and are the principal nutrient-transporting cell type. We previously reported that vitamin D treatment stimulated yolk calcium mobilization and that the vitamin D-dependent Ca2+-binding protein, calbindin-D28K, is present in the yolk sac. We report here the developmental expression and regulation of calbindin-D28K in the yolk sac. Calbindin-D28K is expressed as early as incubation d 3 and is found exclusively within the cytoplasm of endodermal cells. Comparative protein and mRNA analyses of yolk sac and dissociated yolk sac endodermal cells as a function of development and treatment with calcitriol (1,25-dihydroxyvitamin D3) in vitro and in vivo showed a development-specific and vitamin D-inducible expression of calbindin-D28K. Northern analysis revealed the expression of vitamin D receptor mRNA in the yolk sac, beginning as early as d 3, strongly indicating that the extraembryonic yolk sac is an early vitamin D target tissue. Cultured yolk sac endodermal cells should serve as a useful in vitro cell model for analyzing the cellular and molecular mechanisms of vitamin D action.

Animals↗
PubMed1996

Management of ovarian endodermal sinus tumor.

OBJECTIVE: To evaluate the role of combination chemotherapy and the optimal cycles of treatment in improving the prognosis of ovarian endodermal sinus tumor, and to study the relationship between the type of surgical management and the outcome of the disease. PATIENTS AND METHOD: Sixty-three patients with ovarian endodermal sinus tumor were divided into 3 groups according to the postoperative chemotherapy they had received. Group 1 (37 patients) patients were treated with at least 6 cycles of VAC (vincristine, actinomycin-D and cytoxan) or 4 cycles of PVB (cysplatin, vincristine and bleomycin). Group 2 (17 patients) patients were treated with VAC in less than 6 cycles or PVB in less than 4 cycles. Group 3 (9 patients) patients received no VAC or PVB but some other drugs like TSPA, 5FU, MTX and cytoxan in various combinations. The sustained remission rates and survivals were compared among these 3 groups. For patients with full courses of treatment with VAC or PVB (Group 1), different types of surgical management were studied about their relationship with the outcome of the disease. RESULTS: The persistent remission rates are 81.8%, 23.5% and 11.8% for group 1, group 2 and group 3 patients respectively (P < 0.001). The survival curve of group 1 is very much different from that of group 2 and group 3 patients. With full courses of chemotherapy with VAC or PVB, it appears that the different types of surgical managements (unilateral vs bilateral adenectomy; with vs without systemic lymphadenectomy; residual tumor < 2 cm vs > 2 cm) did not show definite relationship with the outcome of the disease. CONCLUSION: Combination chemotherapy with VAC or PVB dramatically improved the prognosis of ovarian endodermal sinus tumor but it should be emphasized that the favorable results could be obtained only when the treatment is given on time and in optimal cycles. Although ovarian endodermal sinus tumor is chemosensitive, appropriate surgical treatment is still important, however, the surgical techniques need some further studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1980

Serum alphafetoprotein (AFP) in patients with germ cell tumors of the gonads and extragonadal sites: correlation between endodermal sinus (yolk sac) tumor and raised serum AFP.

During the last 6 1/2 years, serum AFP has been determined by radioimmunoassay in 387 patients with germ cell tumors of the gonads and extragonadal sites. The histological appearances of all these neoplasms were carefully reviewed. Highly elevated levels of serum AFP were noted in patients with tumors containing endodermal sinus (yolk sac) tumor elements irrespective of the location of the neoplasm or presence or absence of metastatic disease. There was good correlation between the presence and quantity of endodermal sinus (yolk sac) tumor elements within the primary tumor or its metastases and elevated levels of serum AFP. All patients with tumors composed of pure seminoma or dysgerminoma, and teratoma, had normal serum AFP levels. Slightly elevated levels of serum AFP up to 60 ng/mg (upper limit of normal 20 ng/ml) were noted in a few patients with testicular tumors composed of pure embryonal carcinoma, whereas patients with tumors composed of or containing endodermal sinus (yolk sac) tumor elements had serum AFP levels that could be measured in 100's or 1000's of ng/ml. Serum AFP was elevated only in patients with active disease. Serum AFP was determined in 81 patients with gonadal tumors of non germ cell origin and was normal in all these patients. Serum AFP is a very good tumor marker in patients with germ cell tumors composed of or containing endodermal sinus (yolk sac) tumor, irrespective of their location. Serial serum SFP determinations can be used for diagnostic purposes, for monitoring the results of treatment, and for early detection of metastases and recurrences. Serial serum AFP determination is a useful procedure in all patients with germ cell neoplasms and is highly recommended.

Adult↗
PubMed2004

Quantitative screening of embryonic stem cell differentiation: endoderm formation as a model.

Embryonic stem (ES) cells have attracted much attention as a possible source of functional cells for regenerative medicine. Therapeutic use of ES cells requires control over the types and frequencies of cells generated during their in vitro differentiation. Due to the complexity of factors that impact upon ES cell differentiation, novel approaches for the optimization of tissue-specific development are required. This motivates our use of factorial and composite design methods to make empirical investigations more efficient, and to reveal unexpected interactions missed by conventional dose-response analysis. Factorial experiments would benefit from the high content evaluation of a large number of test conditions, necessitating the development of a quantitative screening technology (QST) capable of reporting the absolute number and frequency of target cells. We have developed and validated such a technology for ES cell differentiation analysis using automated fluorescence microscopy, employing endoderm differentiation as a model system. To test this platform, a two-level factorial experiment was carried out to identify major and interactive effects of glucose, insulin, retinoic acid (RA), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) on endoderm formation. RA was found to have inhibitory effects on endoderm formation, while low glucose proved beneficial. QST was demonstrated to be a powerful tool to study factors impacting endoderm-specific ES cell differentiation, and should be applicable to the analysis of a range of ES cell-derived tissues.

Algorithms↗